Normal Pressure Hydrocephalus (NPH) and Alzheimer's Disease (AD) constitute an important public health crisis and may be treated by shunting. However, shunt treatment in NPH has resulted in mixed outcomes and the current treatment has the following problems. Not all patients improve with shunting, using the standard pressure controlling shunts, and, if improvement does occur, it often dissipates in a few years' time. Over-shunting and under-shunting in NPH have been significant clinical problems despite the development of programmable shunts capable of multiple opening pressure settings. AD may also be treated by shunting, but clinical trials have failed to ID 11 entify a therapeutic that alters the progression of disease. Cognitive impairment in NPH and AD is linked to amyloid-beta peptide (Aβ) accumulation and the “amyloid cascade” (Querfurth and LaFerla 2010; Silverberg et al. BRES 2010; Silverberg et al. Lancet Neurol 2003). In aging, NPH and AD there is no increase in AP production; rather, AP clearance from the brain declines (Mawuenyega et al. 2010; Silverberg et al BRES 2010; Silverberg et al J Neurosurg 2002). Improving Cerebrospinal Fluid (CSF) turnover and metabolite clearance could significantly benefit both NPH and AD patients. Aging is the single most important risk factor in the genesis of AD (NIH 2002, Lu 2004, Yankner 2008), and ID 11 iopathic NPH is a disease of elderly patients. A number of Aβ clearance pathway defects as a function of age that play a role in age-dependent Aβ accumulation have been ID 11 entified (Silverberg et al. 2003, 2010a, 2010b, Pascale et al. 2011; Chiu et al. 2012). AP transport at the brain barriers, the blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) is impaired due to age, NPH- and AD-dependent alterations in Aβ transporter expression, decreases CSF production and turnover rates (May et al. 1990, Preston 2001, Silverberg et al. 2001, 2002, 2003, Chiu et al 2012) Improved CSF dynamics in mitigating cognitive decline in these dementias may define a new and more effective treatment option for NPH and AD, and perhaps other proteinopathies as well. Such novel therapy is an urgent public health necessity.
CSF shunt designs and functionality have changed little since their introduction some 50 years ago. They are designed to regulate Intracranial Pressure (ICP) by providing an alternative pathway for CSF to escape from the Central Nervous System (CNS) under the control of a valve, typically “shunting” CSF from one of the lateral ventricles to the peritoneal cavity. The vast majority of traditional available shunts operate as passive pressure relief valves. One notable exception is a hybrid which operates as a pressure relief valve at physiologically low and high pressures and as a flow control (variable resistance valve) over the “normal” range of pressures. A number of the pressure control devices are magnetically-adjustable in that their performance characteristics, the rate of flow as a function of pressure, can be modified after implantation to one of a predetermined number of settings. None of these devices incorporates any means of monitoring shunt outflow nor do they provide information on clinically-significant parameters to clinicians. Assessment of shunt function is difficult as there are currently no means, separate from invasive techniques, to measure pressure or flow through implanted shunts. Their outflow is dependent on patient specific boundary conditions which affect the pressure differential between the input and output of the device. These include conditions such as posture, level of physical activity, sleep (REM) and changes in CSF production. As such, no device available today is capable of draining a known and consistent volume of CSF, or of performing real time modification of performance to accommodate different and or varying patient specific boundary conditions. Pumps and meters are capable of transferring a consistent volume of CSF, independent of patient specific boundary conditions, and may provide a significant advantage over traditional shunts. The primary challenges associated with bringing such devices to market are minimizing power requirements and miniaturization.
NPH is now often treated by CSF shunting and clinical trials have been run to evaluate the efficacy of treating AD by shunting. However in NPH, CSF pressure is normal for much of the time, and in AD it is entirely normal or low. Given the highly variable flow rates associated with traditional shunt performance which are dependent upon the CSF pressure, the valve opening pressure and the conductance of the shunt system 20, results from such usage and trials has been varied. Interestingly, NPH patients implanted with low resistance shunts (those likely to have higher flow rates) have a better outcome than those implanted with higher pressure valves, but at the same time have a higher incidence of subdural fluid collections, a sign of over-shunting (Boone et al. 1998).
By improved control of CSF outflow and incumbent improvement in CSF circulation, a novel shunt system may relieve or reduce the symptoms and suffering of these patients. Currently available shunt systems focus on maintaining a normal ICP with no acknowledgment of the CSF flow rate, whereas novel new shunts as described herein will focus on maintaining normal or improved CSF flow and turnover rates while still monitoring ICP. Turnover is defined as the number of times the total volume of CSF is replaced in a day, which is normally four to five times daily. CSF turnover is a major pathway for clearance of potentially toxic metabolites from the brain, e.g., amyloid and tau protein, particularly important when transport across the brain capillaries becomes less efficient with age.
Currently available shunt systems also lack diagnostic and control capabilities that can be performed by an actively powered and programmable shunt system with appropriate sense inputs. Such sense inputs comprise relevant physiological parameters such as but not limited to parenchymal perfusion, CNS compliance, CSF production, and O2 saturation. They are additionally unable to differentiate between ICP, hydrostatic head (HH), and outflow pressure. This is significant because HH and outflow pressure have little clinical relevance to the treatment and often constitute a source of error and clinical risk. Currently available shunt systems also lack the ability to measure or treat on the basis of CNS compliance, brain perfusion, and other associated characteristic such as CNS frequency response. They lack the means to modify performance as a function of time of day or the outcome of previous treatments. They also lack a means of communicating clinically relevant data to a clinician, such as patient diagnostics, shunt performance, or the occlusion of the shunt. Currently available “programmable” shunts only provide a means to switch between a set of predetermined flow-pressure performance curves and do not address these concerns.